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bioRxiv · 10.1101/2023.07.25.550549

Cobalt-sulfur coordination chemistry drives B12 loading onto methionine synthase

Mascarenhas, R.·Guha, A.·Li, Z.·Ruetz, M.·An, S.·Seravalli, J.·Banerjee, R.
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Abstract

Cobalt-sulfur (Co-S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in Nature. Cobalamin (or vitamin B12) is an essential cobalt-containing organometallic cofactor in mammals, and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination, for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the {beta}-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.

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Mascarenhas, R., Guha, A., Li, Z., Ruetz, M., An, S., Seravalli, J., Banerjee, R.. 2023-07-26. Cobalt-sulfur coordination chemistry drives B12 loading onto methionine synthase. https://doi.org/10.1101/2023.07.25.550549

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